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Diaryl substituted glycolythiourea compounds as well as preparation method and application thereof

A kind of technology of hydantoin thiourea and diaryl group, applied in the field of hydantoin thiourea compounds and preparation thereof, and can solve problems such as treatment failure

Active Publication Date: 2014-08-27
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the mutation of AR allows it to bind to co-activators after combining with traditional AR antagonists, thus causing AR antagonists to become agonists, inducing target gene transcription, leading to treatment failure, which is also one of the main reasons for CRPC

Method used

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  • Diaryl substituted glycolythiourea compounds as well as preparation method and application thereof
  • Diaryl substituted glycolythiourea compounds as well as preparation method and application thereof
  • Diaryl substituted glycolythiourea compounds as well as preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0063] The synthesis of embodiment 1 substituted aniline 3a-3c

[0064] (1) Preparation of N-alkyl-2-substituted-4-nitrobenzamide

[0065] Put 2-substituted-4-nitrobenzoic acid (10mmol) in a 100mL reaction flask, add 30mL of anhydrous tetrahydrofuran, add 3 drops of DMF, stir well at room temperature, until the solid is completely dissolved, put the reaction flask in an ice alcohol bath , slowly add thionyl chloride (12mmol) dropwise, react at room temperature for 1h, evaporate the solvent under reduced pressure, dissolve the remaining solid with anhydrous DMF, and slowly add dropwise to 15ml of tetrahydrofuran solution of methylamine, ethylamine or isopropylamine (2mol / L), evaporate the organic solvent under reduced pressure, extract with ethyl acetate, combine the organic layers, wash with water, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, remove anhydrous sodium sulfate, evaporate under reduced pressure Solvent, to obtain interm...

Embodiment 2

[0075] The preparation of embodiment 2 intermediate compound 4

[0076] Put the intermediate compound 3 (5mmol) and cyclobutanone (10mmol) in a 100mL two-neck flask, add 20mL of 90% glacial acetic acid to dissolve it completely, carefully add sodium cyanide (10mmol), quickly seal it, and reflux at 80°C for 24h. Pour the reaction mixture into 100 mL of ice water, adjust the pH value to neutral, extract with ethyl acetate, combine the organic phases, wash with water, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure to obtain The crude product was separated and purified by silica gel column chromatography to obtain intermediate 4, and the elution system was petroleum ether:ethyl acetate=3:1.

[0077] The intermediate compound 3 used was p-toluidine, p-fluoroaniline, N-isopropyl-4-aminobenzamide, N-ethyl-2-fluoro-4-aminobenzamide or N-isopropyl-2 -Fluoro-4-aminobenzamide, correspondingly, the...

Embodiment 3

[0083] The preparation of embodiment 3 intermediate 6 substituted phenyl isothiocyanates

[0084] C(S)Cl 2 (6.5mmol) and water (11mL) were added to a 25mL round-bottomed flask, stirred thoroughly at room temperature to form a heterogeneous system, and substituted aniline (compound 5) (6mmol) was added to the reaction solution, and reacted at room temperature for 1h to 2.5 h, the reaction solution was extracted with dichloromethane (15mL×3), the organic phases were combined and washed with saturated NaCl (30mL), and the organic phase was washed with anhydrous MgSO 4 After drying, filtering, and evaporating the solvent under reduced pressure, the intermediate compound 6 was separated by silica gel column chromatography, and the elution system was petroleum ether: ethyl acetate volume ratio 6:1.

[0085] The substituted aniline (compound 5) used above is 3-methoxy-4-cyanoaniline, 3-chloro-4-cyanoaniline, 3,4-dicyanoaniline, 2,3,4-trifluoroaniline, 3-Chloro-4-fluoroaniline, 3-br...

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Abstract

The invention discloses diaryl substituted glycolythiourea compounds, the structure of which are shown in a formula (I), wherein R1 is hydrogen, halogen or trifluoromethyl; R2 is hydrogen, halogen, trifluoromethyl, nitrile or alkoxyl; R3 is hydrogen, halogen or nitrile; R4 is hydrogen or halogen; R5 is hydrogen, halogen, methyl, N-methylamine formyl, N-ethylamine formyl, N-isopropylamine formyl and N-cyclopropylamine formyl. The diaryl substituted glycolythiourea compounds disclosed by the invention, particularly 7b-7g, 7i-7k, 7m-7p and 7r-7t, have strong growth inhibiting activity to a hormone-dependent prostate cancer cell LNCaP and can be used for preparing anti-tumor medicines.

Description

technical field [0001] The invention relates to the field of organic compound synthesis and medical application, in particular to thiohydantoin compounds, their preparation method and pharmaceutical application. Background technique [0002] Prostate cancer (PCa) is a common tumor that threatens men's health. In the past decade, the incidence of PCa in my country has shown an obvious upward trend, and has become one of the fastest-growing tumors. The vast majority of prostate cancer cells need to grow and proliferate under the stimulation of androgen (testosterone or dihydrotestosterone DHT), so androgen deprivation therapy (androgen deprivation therapy, ADT, also known as castration therapy) is currently clinically used for prostate cancer First-line endocrine therapy for treatment. Androgen ablation therapy works by blocking androgen production (eg, radical prostatectomy or the gonadotropin-releasing hormone analog GnRH) and blocking endogenous androgen interaction with t...

Claims

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Application Information

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IPC IPC(8): C07D235/02A61K31/4184A61P35/00A61P13/08
CPCC07D235/02
Inventor 赵桂森刘建珍刘波景永奎邢华鲁谢文成张景雅
Owner SHANDONG UNIV
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